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Avian Pathology
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Pharmacokinetics of doxycycline in broiler chickens

A. Anadn , M. R. MartinezLarraaga , M. J. Diaz , P. Bringas , M. C. Fernandez , M. L. FernandezCruz , J. Iturbe & M. A. Martinez
a a a a a a a a a

Departamento de Toxicologa, Instituto de Farmacologa y Toxicologa, CSIC, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040, Madrid, Spain Available online: 12 Nov 2007

To cite this article: A. Anadn, M. R. MartinezLarraaga, M. J. Diaz, P. Bringas, M. C. Fernandez, M. L. FernandezCruz, J. Iturbe & M. A. Martinez (1994): Pharmacokinetics of doxycycline in broiler chickens, Avian Pathology, 23:1, 79-90 To link to this article: http://dx.doi.org/10.1080/03079459408418976

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Avian Pathology (1994) 23, 79-90

Pharmacokinetics of doxycycline in broiler chickens

A. ANADN, M. R. MARTINEZ-LARRAAGA, M. J. DIAZ, P. BRINGAS, M. C. FERNANDEZ, M. L. FERNANDEZ-CRUZ, J. ITURBE & M. A. MARTINEZ Departamento de Toxicologa, Instituto de Farmacologa y Toxicologa, CSIC, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain

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SUMMARY Doxycycline was given to two groups of eight chickens at a dose of 20 mg/kg of body weight, intravenously (i.v.) or orally. Plasma concentration was monitored serially for 12 h after each administration. Another group of 30 chickens was given 20 mg/kg orally every 24 h for 4 days, and plasma and tissue concentrations determined serially after the last administration. Concentrations of doxycycline were measured using high-performance liquid chromatography. Pharmacokinetic variables were calculated, using a two-compartment open model. The elimination half-life and the mean residence time for plasma were 6.03 0.45 and 7.48 0.38 h, respectively, after oral administration and 4.75 0.21 and 2.87 0.11 h, respectively, after i.v. administration. After single oral administration, doxycycline was absorbed rapidly, with Tmax of 0.35 0.02 h. Maximum plasma concentration was 54.58 2.44 /ml. Oral bioavailability of doxycycline was found to be 41.33 2.02%. Doxycycline was widely distributed in tissues and considerable concentrations were found following oral administration of 20 mg/kg on four successive days. The results indicate that doxycycline concentrations were cleared slowly and were at or below the accepted drug tolerance levels in the marker tissues within 5 days after dosing. INTRODUCTION Doxycycline (a-6-deoxy-5-hydroxytetracycline) is a 'second generation' tetracycline mainly active against Gram-positive and Gram-negative aerobic and anaerobic bacteria. Spirochetes, Mycoplasma species, Rickettsia species, Chlamydia tracomatis and C. psittaci, Ureaplasma urealyticum, Erlichia species and Anaplasma species also demonstrate good susceptibility (Riond and Riviere, 1988). Doxycycline has a low affinity for calcium and is relatively more stable in aqueous solution (Fabre et al, 1971; Welling et ah, 1977). It has a high relative liposolubility (5- to 10-fold increases in relation to older tetracyclines) which readily compensates for the high protein binding (Barza et al, 1975; Fourtillan & A preliminary report of this study was presented at the EuroResidue II, Conference of Residues of Veterinary Drugs in Food, Veldhoven, The Netherlands, May 3-5, 1993. Received 13 April 1993; Accepted 24 June 1993. 79

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against staphylococci, streptococci and anaerobic bacteria (English, 1966; Williamson, 1968; Chow et al, 1975). All these characteristics support the notion that doxycycline may have therapeutic usefulness in veterinary medicine. Since doxycycline was introduced into modern drug therapy by Schach Von Wittenau & Delahunt (1966) many of its pharmacokinetic and pharmacodynamic characteristics have been studied in detail mainly in humans (Fabre et al, 1971; Saux et al, 1981; Cars and Ryan, 1988). Doxycycline has several important advantages over other tetracycline analogues: absorption is almost complete, tissue penetration is good, elimination is slower necessitating only one daily dose, the elimination rate is irrespective of renal function and more than 90% of the dose is recovered as undegraded drug from urine and faeces. Although few pharmacokinetic studies have been done in birds, doxycycline is often used to treat avian infectious diseases such as colibacillosis, salmonellosis, staphylococcosis, mycoplasmosis and chlamydiosis, (George et al, 1977; Jakoby, 1979; Gylstorff et al, 1984; Goren et al, 1988; Dorrestein et al, 1990). The purpose of the present study was to determine the pharmacokinetic values of doxycycline hydrochloride in broiler chickens so that rational therapeutic regimens may be formulated. The potential tissue residues were also evaluated in order to establish the safety of doxycycline in this food-producing animal species in the context of public health. MATERIALS AND METHODS

Chickens and protocol

Forty-six 40-day-old 2.5 kg male broiler chickens (Hubbard X Hubbard) were purchased at a poultry farm and placed individually in cages in the animal house of this laboratory 1 week before administration of the medication. Clinical signs of disease were not apparent. The animal house was maintained at 25 2C and at 45 to 65% humidity. Food and water were supplied ad libitum. Experimental design Birds were allotted to three groups. Groups 1 and 2 (eight chickens/group) were given single oral or intravenous (i.v.) administered doxycycline at 20 mg/kg body weight. Chickens of group 3 (n = 30) were given 20 mg of doxycycline/kg orally daily for 4 consecutive days. Doxycycline hydrochloride was dissolved in distilled water to a total volume of 0.5 or 2 ml prior to i.v. or oral administration, respectively. Doxycycline was administered i.v. in the right brachial vein or orally directly into the crop, using a thin plastic tube attached to a syringe. Food was withheld for 12 h before each oral dosing. For chickens of groups 1 and 2, blood samples were drawn via a cannula from the left brachial vein into heparinized syringes at 0.25, 0.33, 0.5, 1, 2, 4, 6, 8 and 12 h after drug administration. Plasma was separated after centrifugation and stored at 20C until assayed for doxycycline concentration.

PHARMACOKINETICS OF DOXYCYCLINE IN BROILERS

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Group 3 chickens were killed by exsanguination (six chickens time) at 12, 24, 48, 72 and 120 h after the last doxycycline dose. Blood, kidney, liver, lung and muscle samples were obtained, carefully weighed and kept at 20C until assayed.

Doxycycline assay
The concentration of doxycycline was measured using high-performance liquid chromatography (HPLC) (Bocker, 1980). Plasma, muscle, liver and kidney samples were separately extracted. Plasma samples (0.5 ml) were mixed with 0.5 ml 0.03M H 3 PO 4 ; after 15min, 2 ml acetonitrile-buffer (0.01M NaH 2 PO 4 , pH 2.4) (50:50) was added. Five minutes later most of the precipitated proteins were spun down (2500 g for 10 min), and the supernatant collected and frozen ( - 20C) until HPLC assay. Tissue sample was homogenized in ice-cold 0.03 M NaH 2 PO 4 (1 part organ + 4 parts buffer) ultrasonically (1 min at 2.5 A using a titanium probe on a Labsonic U, B. Braun-Biotech SA). After 15 min, 1 ml of the homogenate was mixed with 2 ml acetonitrile-buffer (0.01M NaH 2 PO 4 , pH 2.4) (50:50) and centrifuged (2500^ for 10 min). For the chromatographic analysis, 20- or 100 fi\ aliquots of the supernatant were injected into the HPLC system (model LC-6A with UV spectrophotometric detector model SPD-6A and data processor model Chromatopac CR-6A, Shimadzu) equipped with Lichrosorb RP8 column (particle size 5 /an; 15 X 0.4 cm) (Merck). The mobile phase was 0.01M NaH 2 PO 4 in water-acetonitrile, 73:27, pH 2.4, and flow-rate of 1.5 ml/min was used. Chromatography was performed at 25 2C with detection at 357 nm. Peak areas in the sample chromatograms were quantitated by use of the external standard technique, using a standard solution of doxycycline as reference. The standard curves were linear between 0.025 and 5 /*g/ml. The method used was selective for the substance analysed; endogenous interference was not observed on chromatograms. The recovery of doxycycline from plasma and tissues was 98% when the doxycycline concentration was not higher than 100 ^g/ml. The lower detection limit was 25 ng/ml. The intra-and inter-assay coefficients of variation were < 5 % .

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Data analysis
Plasma concentration-time data were fitted to a two-compartment open model for kinetic analysis. Pharmacokinetic variables were obtained by use of an extended least-squares nonlinear regression programme (Sheiner, 1981). The plasma curves of doxycycline after oral and i.v. administration were obtained for each chicken and fitted to the following exponential equations:

Where C is the plasma concentration, Au

A2 and A3 are mathematical

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coefficients; a is the hybrid rate constant for the distribution phase; /?, is the hybrid rate constant for the terminal elimination phase; and Kn is the first-order absorption rate constant. These equations were chosen by use of the minimal Akaike information criterion estimation (Yamaoka et a/., 1978). The error model chosen to estimate the curve-fitting variables was proportional to the power of prediction. The absorption half-life (tQ, the half-life at a phase (tl), the half-life at P phase (tip), the distribution rate constants for transferring the drug from the central to the peripheral compartment (K^) and from the peripheral to the central compartment (K2\) and the elimination rate constant (Ki0) were calculated by standard equations (Baggot, 1977). After oral or i.v. administration, the areas under the concentration-time curves (AUC) were calculated as follows:

AUC = (AJa)
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or
The total plasma clearance [CL = (dose/kg) X FIA UC or CL = (dose/kg)/AUC] The mean residence time l) X 1/AUC or MRT= (AM +A2/02) X 1/AUC]. The apparent volume of distribution [V^tm) = (dose/kg) XF/AUCX /} or Pd(arca) = (dose/kg)//J t/C X /J] and at steady state (only for i.v. administration, The maximum concentration in plasma after oral administration (Cmax) and the time needed to reach Cm!a(Tmix) were also evaluated. The oral bioavailability of doxycycline was calculated from the ratio between the value of AUCon\ for each chicken and the mean value of AUCw for the eight chickens used in the i.v. administration study, F= (AUCO^/AUCJV). Complete absorption was determined on the basis of AUCiv, which represents the mean AUC for the eight chickens to which doxycycline was administered. Because of the small individual variation in AUCw and the fact that the same eight chickens were not available for oral and i.v. studies, the mean AUCjy, rather than AUCjy for each chicken, was used to estimate bioavailability after oral administration. Mean pharmacokinetic variables were obtained by averaging the variables calculated for drug disposition after each administration in each chicken. Differences in pharmacokinetic data between dosing routes were analyzed statistically by the Mann-Whitney 7-test. Differ-

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400200100-

1
c

402010-

rati

42I 6

1 10

I 11

12

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Time (h)

Figure 1. Plasma concentrations of doxycydine after (O) single oral or (9) i.v. administration of 20 mg/kg. Data are expressed as mean SEM values for eight chickens. Symbols without bars indicate that the SEM is within the symbols.

ences of P< 0.05 were considered significant. All data were tabulated as mean SEM. RESULTS The mean plasma concentrations of doxycycline after a single oral or i.v. dose of 20 mg/kg are shown in Figure 1. Following oral and i.v. administration, the plasma concentration-time curve exhibited a biphasic decline. A good fit of observed data to a two-compartment open model was obtained. The values of the kinetic parameters which described the absorption and disposition kinetics of doxycycline are given in Table 1. Concentrations greater than 1 jig/ml (potential therapeutic value) were maintained for at least 12 h post oral administration. The values for ria and 7 ^ in plasma were 0.109 0.008 and 0.35 0.02h, respectively. The maximum concentration for the 20 mg/kg dose was 54.85 2.44/ig/ml. Bioavailability of doxycycline after oral administration was 41.33 2.02% (Table 1). Doxycycline was distributed more quickly after i.v. than after oral dosing, the distribution half-life (fi^) being 0.23 0.01 and 0.40 0.04 h, respectively; these values were significantly (P< 0.05) different. Doxycycline levels in plasma declined slowly (Figure 1) and the total plasma clearance was 0.0401/h/kg (Table 1) irrespective of the dosing route. The i.v. elimination half-life (tip) was smaller than that for oral administration (P< 0.05). This difference is probably the result of continued absorption of doxycycline from the gastrointestinal tract during the elimination phase, thereby, prolonging the tip of the drug. The mean tissue concentrations after daily oral administration are given in

84

A. ANAD6N ETAL. Table 1. Doxycycline pharmacokinetic variables in eight chickens aftersingle oralori.v. administration of 20 mg/kg of body weight Route of administration Variable Ai O/ml) A 2 Oug/ml) A 3 (jig/ml) Oral Mean SEM 90.46 8.70 22.25 2.59 128.10 12.77 1.81 0.14 0.12 0 . 0 1 6.55 0.45 0.40 0.04 6.03 0.45 0.11 0.01 0.33 0.02 0.98 0.10 0.55 0.06 0.40 0.02 214.21 10.46 41.33 2.02 7.48 0.38 0.040 0.001 1.93 0 . 1 5 2.45 0.21 1.43 0.20 54.58 2.44 0.35 0.02 intravenous Mean SEM

945.01 97.08 30.78 4.20 2.99 0.11 0.15 0.01 0.23 0.01* 4.75 0.21* 0.28 0.02 0.11 0.01 1.02 0.06 0.24 0.02 1.87 0.09 518.26 40.44 2.87 0.11* 0.040 0.003 4.37 0.33 0.56 0.05 0.13 0.02

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a(h"') /?(h-') *T.(h-') ^(h) ^(h) ti.(h)

KdC^a) (I/kg)

KnCh"1) Ki, (h' 1 )

^io (h' 1 )

VdM (I/kg)

/lt/C (mg/h/1) P(%) MRTQO

CL (1/h/kg)
/C12/K21
^12/^10

K21/JC10

Cmax (/xg/ml) 7*max(h)

*Significant (P< 0.05) difference between dosing routes.

Table 2. Plasma concentration of doxycycline at 12 h after the last dose was the same whether the drug was given once or 4 times. The tissue-to-plasma concentration ratios (calculated 12 h after dosing) were for kidney, 0.53 0.05; for lung, 0.50 0.07; for liver, 0.35 0.04 and for muscle, 0.23 0.03. Doxycycline was eliminated slowly from tissues. It was estimated that mean tissue doxycycline concentrations of 0.028 to 0.20 /xg/g persisted for 5 days after treatment (Table 2). DISCUSSION Although the pharmacokinetic variables of doxycycline have been studied in mammals the drug's kinetic profile in broiler chickens has received minimal investigation. Its disposition after i.v. or oral administration in chickens could be described adequately by a two-compartment open model. Experiments performed in mammals (Ziv & Sulman, 1974; Michel et al, 1984; Jha et al., 1989; Riond et al, 1989) have led to the same conclusion. Disappearance of the drug from the plasma of chickens was characterized by an initial rapid distribution phase

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Table 2. Tissue concentrations of doxycycline in chickens after oral doses of 20 mg/kgfor 4 days Tissue Kidney Time after the last dose
12h Id 2d 3d 5d 12h Id 2d 3d 5d

Doxycycline 3.01 0.36 1.92 0.33 1.50 + 0.28 0.93 + 0.11 0.17 0.03 1.93 0.20 0.90 + 0.14 0.87 0.11 0.54 0.11 0.12 0.03 2.54 0.25 1.68 0.22 0.77 + 0.12 0.12 + 0.02 0.03 0.005 1.32 + 0.16 1.18 + 0.23 0.69 0.09 0.26 0.10 0.06 + 0.02

Liver

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12 h Lung
Id 2d 3d 5d

12 h Muscle
Id 2d 3d 5d

* Each value is the mean SEM for six chickens.

followed by a slower elimination phase. Doxycycline distributed very rapidly in body fluids and tissues as evidenced by the high values for distribution rate constant (short distribution half-life) and the high values of K12/K21 (Table 1). Doxycycline is highly lipophilic and would be expected to be distributed widely in the chicken. Nevertheless, the V^m*) of 0.28 0.02 I/kg determined in the present study was much lower than that reported for other species: 0.75 I/kg in adult humans (Raghuram & Krishnaswamy, 1982), 1.38 I/kg in calves (Riond et al, 1989), 1.5 to 3.5 I/kg in dogs (Michel et al, 1979), 2.28 I/kg in cows and ewes (Ziv & Sulman, 1974), 4.5 to 7 I/kg in rats (Michel et al, 1984) and 9.78 I/kg in goats (Jha et al., 1989). The lower value of apparent volume of distribution found in the present study may be attributed to higher plasma protein binding, as well as a lower gut reabsorption of drug in the chicken. Additional studies will be necessary to clarify this hypothesis. The doxycycline salt used also could affect the result (Saux et al, 1981; Michel et al, 1984). Doxycycline has a shorter tip in chickens than in other domestic species. Qualitative and quantitative differences in dosage and drug elimination may have contributed to this result. Metabolism of doxycycline does not seem to be the cause of the differences in drug elimination among species. Photodiode array detection of an HPLC column effluent and mass-spectrometric analyses of serum

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and urine of calves, pigs, cats and dogs confirmed studies in man, which suggested that doxycycline is not metabolized (Fourtillan et al, 1980; Nelis & De Leenheer, 1981; Riond et al, 1989, 1990; Riond & Riviere, 1990). The elimination half-life (tip) found in chickens was similar to that recorded in young pigs (Riond et al, 1990) following an i.v. dose of 20 mg/kg. This may be attributed to the similar volume of distribution obtained in chickens and young pigs. If the extent of binding to plasma proteins is similar in different species, it may be postulated that in chickens and young pigs less drug binds to tissue or, possibly, there is less intracellular penetration. The extent of doxycycline binding to chicken serum proteins has not been tested. The tip of doxycycline was longer than the tty of tetracycline (65 mg/kg in 2.7 h) obtained in broilers (Anadon et al, 1985). After oral administration, doxycycline was rapidly, but only partially, absorbed. Average bioavailability of 20 mg/kg was 41%; lower than that (90-95%) found in mice and humans (Bocker & Estler, 1981; Fourtillan et al, 1980). The mean maximum plasma concentration of 54.58 fig/ml reported here after the single oral administration of 20 mg/kg was greater than the value reported by Archimbault et al (1983) in laying-hens (5.3 /ig/ml) after oral administration of 10 mg/kg. On the other hand, the mean T"max of doxycycline was 0.35 h in chickens, less than that estimated in laying hens (Archimbault et al, 1983) or rats and humans (Michel et al, 1984). Considering therapeutic ranges reported in birds (Wachendorfer, 1973; Goren et al, 1988) and in vitro minimal inhibitory concentrations of susceptible Gram-negative and Gram-positive organisms (Riond & Riviere, 1988) an approximate target concentration could be between 0.5 and 4 /zg/ml. In our study, the plasma doxycycline concentration at 12 h for the 20 mg/kg dosage was 5.29 0.30 /ig/ml. On this basis, the plasma doxycycline concentration achieved after oral administration of 20 mg/kg/day, should be appropriate for control of avian diseases. The high peak blood concentrations ( > 50 /ig/ml) might also suggest it could be used effectively at a lower dose. Previous studies have shown that doxycycline is readily available for tissue distribution (Schach Von Wittenau & Delahunt, 1966; Bocker & Estler, 1981; Michel et al, 1984). In this study, high concentrations were found in kidney, liver, lung and muscle after a dosing regimen of 20 mg/kg daily for 4 days. Doxycycline is one of the most lipid soluble tetracycline derivatives (Cunhua et al, 1982). However, in the chicken we found that levels in kidney, liver, lung and muscle were lower than the concurrent plasma levels 12 h after dosing. This finding disagreed with that reported in rabbit by Cars and Ryan (1988) who found concentrations in excess of serum levels in muscle. Thus, it may be that the degree of tissue penetration of doxycycline in chickens is lower than in other species. Doxycycline is usually administered orally in chickens; thus, we studied a dosing regimen of 20 mg/kg day for 4 days to estimate tissue-depletion of doxycycline. Substantial concentrations of doxycycline were still detected at 5 days after termination of treatment. In conclusion, doxycycline has useful pharmacokinetic characteristics for effec-

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tive treatment of infections in poultry. In the chicken, it has been found to be absorbed after oral administration and a therapeutic concentration is achieved in plasma. For oral administration of 20 mg/kg on four successive days, a withdrawal time of 5 days might be adequate to predict that the concentrations in edible tissues are below accepted drug tolerance levels of 0.600 fig/g in kidney, 0.300 /ig/ g in liver and 0.100 /zg/g in muscle (EEC, 1993). From a public health viewpoint, it is important to consider this recommendation in the light of an overall risk-benefit assessment for consumers of this food-producing animal.

ACKNOWLEDGEMENTS
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This research was supported by the Comisin Interministerial de Ciencia y Tecnologa, Plan Nacional de Investigacin Cientfica y Desarrollo Tecnolgico, Programa Nacional de Salud y Farmacia, Project SAF 92-0203 and by the Comunidad de Madrid, Project N 172/92, Spain.

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SCHACH VON WITTENAU, M . & DELAHUNT, C.S. (1966). The distribution of tetracyclines in tissues of dogs after repeated oral administration. Journal of Pharmacology and Experimental Therapeutics, 152, 164169. SHEINER, L.B. (1981). ELSFIT A Program for the Extended Least Squares Fit to Individual Pharmacokinetic Data. A Technical Report of the Division of Clinical Pharmacology (San Francisco, University of California Press). WACHENDORFER, J.G. (1973). Epidemiology and control of psittacosis. Journal of the American Veterinary Medical Association, 162, 298-303.
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doxycycline in fasted and nonfasted subjects. Antimicrobial Agents and Chemotherapy, 11, 462-469. WILLIAMSON, G.M. (1968). The in vitro activity of vibramycin (doxycycline). Chemotherapy, Supplementum, 13, 1-6. YAMAOKA, K., NAKAGAWA, T. & UNO, T. (1978). Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. Journal of Pharmacokinetics and Biopharmaceutics, 6, 165-175. Ziv, G. & SULMAN, F.G. (1974). Analysis of pharmacokinetic properties of nine tetracycline analogues in dairy cows and ewes. American Journal of Veterinary Research, 35, 1197-1201.

PHARMACOKINETICS OF DOXYCYCLINE IN BROILERS

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RESUME Pharmacocintique de la doxycycline chez le poulet de chair

Deux groupes de huit poulets de chair ont reu une dose de 20 mg/kg de poids vif de doxycycline par voie orale et par voie intraveineuse. Aprs chaque administration du mdicament, les concentrations plasmatiques de doxycycline ont t values diffrents intervalles de temps, pendant 12 h. Un autre groupe de 30 poulets a t trait oralement avec 20 mg de doxycycline/kg par 24 h, pendant 4 jours. Les concentrations plasmatiques et tissulaires de doxycycline ont t dtermines diffrents intervalles de temps par Chromatographie liquide haute performance. Les paramtres pharmacocintiques ont t calculs conformment un modle bicompartimental ouvert. La demi-vie d'limination et le temps moyen de persistance dans le plasma ont t respectivement de 6,03 0,45 et de 7,48 0,38 h aprs administration orale et de 4,75 0,21 et 2,87 0,11 h respectivement aprs administration intraveineuse. La doxycycline, aprs administration orale d'une dose unique, a t absorbe rapidement avec un T max de 0,35 0,02 h. La concentration plasmatique maximale a t de 54,58 2,44 g/ml. La biodisponibilit orale de la doxycycline a t de 41,33 2,02 % et le produit a t largement distribue dans les tissus. Des concentrations importantes de doxycycline ont t observes lors de l'administration orale de doxycycline la dose de 20 mg/kg pendant 4 jours conscutifs. Ces rsultats indiquent que la doxycycline s'limine lentement des tissus et que les concentrations taient gales ou infrieures aux niveaux de tolrance accepts dans les tissus cibles dans les 5 jours suivant l'administration de la dernire dose.

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ZUSAMMENFASSUNG Pharmakokinetik von Doxycyclin bei Masthhnern

Doxycyclin wurde zwei Gruppen von je acht Masthhnern in der Dosis von 20 mg/kg Krpergewicht intravens (i.v.) oder oral verabreicht. Die Plasmakonzentration wurde nach jeder Applikation 12 Stunden lang regelmig kontrolliert. Einer anderen Gruppe von 30 Hhnern wurde 4 Tage lang alle 24 Stunden 20 mg/kg oral verabreicht, und die Plasma- und Gewebskonzentrationen wurden in regelmigen Abstnden bestimmt. Die Doxycyclin-Konzentrationen wurden mit Hilfe der HPLC gemessen. Die pharmakokinetischen Variablen wurden mit Hilfe eines offenen Zwei-Kompartiment-Modells berechnet. Die Eliminations-Halbwertzeit und die mittlere Verweildauer im Plasma waren 6,03 0,45 bzw. 7,48 0,38 Stunden nach oraler Verabreichung und 4,75 0,21 bwz. 2,87 0,11 Stunden nach i.v. Applikation. Nach einmaliger oraler Gabe wurde Doxycyclin rasch resorbiert, mit einer Tmax von 0,35 0,02 Stunden. Die maximale Plasmakonzentration betrug 54,58 2,44 g/ml. Die Bioverfgbarkeit von oral verabreichtem Doxycyclin betrug 41,33 2,02%. Doxycyclin wurde weit in den Geweben verbreitet, und betrchtliche Konzentrationen wurden an den 4 Tagen nach oraler Applikation von 20 mg/kg nachgewiesen. Die Ergebnisse zeigen, da Doxycyclin langsam eliminiert wurde und die Konzentrationen in den ausgewhlten Geweben innerhalb von 5 Tagen nach der Applikation nicht ber dem akzeptierten Vertrglichkeitsniveau lagen.

RESUMEN Farmacocintica de la doxiciclina en pollos broiler

Se administr doxiciclina a dos grupos de ocho pollos broiler a una dosis de 20 mg/kg de peso corporal por va intravenosa (i.v.) y oralmente. Se registr la concentracin plasmtica a intervalos durante 12 horas tras cada administracin del frmaco. Otro grupo de 30 pollos recibi una dosis de 20 mg/kg de peso corporal por va oral cada 24 horas durante 4 das y se

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A. ANADN ETAL.

determinaron seriadamente sus concentraciones plasmticas y tisulares tras la ltima administracin. Se emple para ello el mtodo de cromatografia lquida de alta resolucin. Se calcularon las variables farmacocinticas empleando un model abierto bicompartimental. La vida media de eliminacin y el tiempo medio de residencia para el plasma fue de 6.03 0.45 y 7.48 0.38 h respectivamente, tras la administracin oral y 4.75 0.21 y 2.870.11 h, respectivamente, tras la administracin i.v. Despus de una sola administracin por va oral, la doxiciclina se adsorbi rpidamente, con T max0.35 0.02 h. La concentracin plasmtica mxima fue de 54.58 2.44 g/ml. La biodisponibilidad de la doxiciclina va oral fue de 41.33 2.02 %. La doxiciclina se distribuy ampliamente en los tejidos y se encontraron unas concentraciones elevadas cuando la doxiciclina se administr por va oral (20 mg/kg) durante 4 das consecutivos. Estos resultados indican que la doxiciclina se elimina lentamente de los tejidos, estando al nivel o por debajo de los niveles de tolerancia aceptados en los tejidos marcadores a los 5 das de haber administrado la ltima dosis.

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